The use of cocaine and amphetamines remains a global problem. Drug addiction involves the complicated interplay between genetics, environment and neuronal changes. Studies have shown that stress, primarily social stress, has a robust correlation with drug abuse, increasing the likelihood of addiction, craving and relapse. Investigation of the cellular changes involved in sensitization to social stress and psychostimulants will shed light on the mechanisms modulating addictive processes. The studies proposed in this fellowship application will examine the dialogue between genes and environment and the impact this has on sensitivity to cocaine and amphetamine by using C57BL/6 and DBA/2 mice, two strains divergent on numerous phenotypes, in experiments of social defeat stress sensitization and subsequent psychostimulant sensitization and cocaine self-administration. The second aim of this proposal is to characterize the underlying neural adaptations that occur in the social defeat stress-sensitized animal, using imunohistochemical techniques. The medial prefrontal cortex has been implicated in both stress and reward. Clarifying the role of the serotonergic pathway from the dorsal raphe nucleus to the medial prefrontal cortex in stress and addiction may lead to the development of pharmaceutical agents in the treatment of psychostimulant addiction.